Epidithiodiketopiperazine (ETP) natural products are a class of structurally complex fungal metabolites that exhibit biological properties including antiviral, antiproliferative, and antibacterial activities. The goal of the proposed research is to develop new synthetic methods and strategies for the synthesis of dihydrooxepine and pyrrolidinoindoline ETP natural products. The development of efficient chemical syntheses of ETP natural products is expected to facilitate the study of their biological properties, and demands innovative new methods to prepare dihydrooxepine and pyrrolidinoindoline core motifs. The proposed research comprises two projects, the first of which targets the natural products aranotin (2) and MPC1001B (5), and is expected to contribute new transition-metal catalyzed methods for the preparation of dihydrooxepines. In addition, the first comprehensive studies of ETP formation in the presence of a dihydrooxepine moiety will be carried out. The specific aims are: 1.1) to develop transition metal-catalyzed cycloisomerization reactions to prepare dihydrooxepines; 1.2) to complete a total synthesis of the antiviral natural project aranotin (2); 1.3) to complete a total synthesis of the antiproliferative natural product MPC1001B (5). The second project targets pyrrolidinoindoline ETPs such as 11-deoxybionectin A (8). To this end, a new enantioselective formal [3+2] cycloaddition to prepare pyrrolidinoindolines directly from indoles will be developed. The specific aims are: 2.1) to develop catalytic asymmetric formal [3+2] cycloaddition reactions to prepare pyrrolidinoindolines; 2.2) to study and elucidate the mechanism of catalytic asymmetric pyrrolidinoindoline formation; 2.3) to complete a total synthesis of 11-deoxybionectin A (8). Synthetic access to ETPs such as 2, 5, and 8, is expected to permit studies aimed at deepening our understanding of the underlying mechanisms of their biological properties. Through collaborations with the City of Hope Cancer Center and the Broad Institute of Harvard and MIT, these natural products and synthetic derivatives will be evaluated as biological probes and potential therapeutics for the study and treatment of cancer and infectious disease. It is anticipated that these studies will result in the development of new chemical reactions, further our fundamental understanding of organic and organometallic chemistry, and contribute valuable information on the chemistry and biology of two distinct families of ETP natural products.